Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes.

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.

Modeling mortality prediction in older adults with dementia receiving COVID-19 vaccination.

OBJECTIVE: This study compared COVID-19 outcomes between vaccinated and unvaccinated older adults with and without cognitive impairment. METHOD: Electronic health records from Israel from March 2020-February 2022 were analyzed for a large cohort (N = 85,288) aged 65 + . Machine learning constructed models to predict mortality risk from patient factors. Outcomes examined were COVID-19 mortality and hospitalization post-vaccination. RESULTS: Our study highlights the significant reduction in mortality risk among older adults with cognitive disorders following COVID-19 vaccination, showcasing a survival rate improvement to 93%. Utilizing machine learning for mortality prediction, we found the XGBoost model, enhanced with inverse probability of treatment weighting, to be the most effective, achieving an AUC-PR value of 0.89. This underscores the importance of predictive analytics in identifying high-risk individuals, emphasizing the critical role of vaccination in mitigating mortality and supporting targeted healthcare interventions. CONCLUSIONS: COVID-19 vaccination strongly reduced poor outcomes in older adults with cognitive impairment. Predictive analytics can help identify highest-risk cases requiring targeted interventions.

Exploring the Self-Reported Physical and Psychological Effects in a Population Exposed to a Regional Conflict.

BACKGROUND: Conflict profoundly impacts community health and well-being. While post-conflict research exists, little is known about initial effects during active hostilities. OBJECTIVE: To assess self-reported changes in health behaviors, distress, and care access within one month of regional warfare onset in a conflict-affected community. METHODS: An online survey was conducted in November 2023 among 501 residents (mean age 40.5 years) of a community where war began October 7th. Measures evaluated physical health, mental health, diet, substance use, sleep, weight changes, and healthcare access before and after the declaration of war. RESULTS: Relative to pre-war, respondents reported significantly increased rates of tobacco (56%) and alcohol (15%) consumption, worsening sleep quality (63%), elevated distress (18% sought help; 14% needed but didn't receive it), and postponed medical care (36%). Over a third reported weight changes. Distress was higher among females and those endorsing maladaptive coping. CONCLUSION: Within one month, substantial impacts on community psychosocial and behavioral health emerged. Unmet mental health needs and risk-taking behaviors were early indicators of conflict's health consequences. Continuous monitoring of conflict-affected communities is needed to inform tailored interventions promoting resilience and prevent entrenchment of harms over time.

Optimising wound monitoring: Can digital tools improve healing outcomes and clinic efficiency.

BACKGROUND: Chronic wounds present significant challenges for patients and nursing care teams worldwide. Digital health tools offer potential for more standardised and efficient nursing care pathways but require further rigorous evaluation. OBJECTIVE: This retrospective matched cohort study aimed to compare the impacts of a digital tracking application for wound documentation versus traditional manual nursing assessments. METHODS: Data from 5236 patients with various wound types were analysed. Propensity score matching balanced groups, and bivariate tests, correlation analyses, linear regression, and Hayes' Process Macro Model 15 were utilised for a mediation-moderation model. RESULTS: Digital wound tracking was associated with significantly shorter healing durations (15 vs. 35 days) and fewer clinic nursing visits (3 vs. 5.8 visits) compared to standard nursing monitoring. Digital tracking demonstrated improved wound size reduction over time. Laboratory values tested did not consistently predict healing outcomes. Digital tracking exhibited moderate negative correlations with the total number of nursing visits. Regression analysis identified wound complexity, hospitalizations, and initial wound size as clinical predictors for more nursing visits in patients with diabetes mellitus (p < .01). Digital tracking significantly reduced the number of associated nursing visits for patients with peripheral vascular disease. CONCLUSION: These findings suggest that digital wound management may streamline nursing care and provide advantages, particularly for comorbid populations facing treatment burdens. REPORTING METHOD: This study adhered to STROBE guidelines in reporting this observational research. RELEVANCE TO CLINICAL PRACTICE: By streamlining documentation and potentially shortening healing times, digital wound tracking could help optimise nursing resources, enhance wound care standards, and improve patient experiences. This supports further exploration of digital health innovations to advance evidence-based nursing practice. PATIENT OR PUBLIC CONTRIBUTION: This study involved retrospective analysis of existing patient records and did not directly include patients or the public in the design, conduct, or reporting of the research.

Evolution of EEG Findings in Pontocerebellar Hypoplasia Type 2A: Normal EEG in the First Few Months followed by Abnormal Tracing over the Years.

Pontocerebellar hypoplasia (PCH) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by cerebellar and pontine hypoplasia, progressive microcephaly, and developmental delay. Ten types of PCH have been described; PCH type 2A (PCH2A) due to a mutation in TSEN54 is the most frequent. Seizures have been reported in the large majority of patients. The probability of epilepsy developing increases with age, along with difficulties in differentiating seizures from dyskinetic movements. The aim of the present report was to describe the clinical symptoms and electroencephalogram (EEG) changes over time in three patients of Israeli Arab origin with PCH2A. All three, including two siblings and their first cousin, were homozygous for the TSEN54 p.A304S mutation. The patients demonstrated profound psychomotor retardation, severe spasticity and contractures, choreoathetoid movements, and seizures. The magnetic resonance imaging (MRI) scans and EEGs were reviewed by an experienced neuroradiologist and epileptologist, respectively. The MRI scans revealed a dragonfly-like cerebellar pattern in all patients. Despite the normal early EEG findings, all patients had characteristic features of epilepsy, with tonic seizures starting in the first days to months followed by focal to bilateral tonic-clonic seizures in early childhood which continued to adolescence. In conclusion, patients with PCH2A due to the missense mutation p.A304S in TSEN54 exhibit profound psychomotor delay, movement disorders, and intractable epilepsy. An evolution of EEG abnormalities and seizure semiology occurs over time. Similar to several other genetic epileptic encephalopathies, the normal early EEG tracing does not rule out the later occurrence of epilepsy.

Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.

OBJECTIVE: The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. METHODS: Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. RESULTS: The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. INTERPRETATION: A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.

Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum.

Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.

The molecular and phenotypic spectrum of IQSEC2-related epilepsy.

OBJECTIVE: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. METHODS: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. RESULTS: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. SIGNIFICANCE: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).

Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.

OBJECTIVE: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. METHODS: Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. RESULTS: Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. SIGNIFICANCE: Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.

Conflict-Related Breakdowns in Routine Medical Care - Longitudinal Outcomes for Civilians with Pre-Existing Cognitive Impairment.

Individuals with dementia face increased vulnerability during crises like armed conflicts. However, little is known about how conflicts affect dementia care delivery and patients' health. We conducted a longitudinal cohort study using medical record data. The study included 23,733 adults aged≥65 years with a diagnosis of dementia and 249,749 matched adults without dementia. Data were collected at baseline (March-October 2023), and two follow-up timepoints (December 2023 and February 2024), bracketing an armed conflict between Israel and Palestinian militant groups that began on October 7, 2023. We compared changes over time in clinical characteristics, medication use, healthcare utilization, costs between groups. Dementia prevalence was stable, but psychotropic medication use declined more sharply in those with dementia. Rates of depression diagnoses fell, and obesity rose in both groups. Healthcare utilization decreased substantially post-conflict, with fewer outpatient visits, hospitalizations, and emergency visits. Cost divergence between groups also increased over time. Machine learning identified shifting clusters of service users from high to mainly low users' post-conflict. The conflict severely disrupted routine dementia care and altered health behaviors. Flexible service delivery and access promotion strategies are needed to support vulnerable populations like people with dementia during crises.

Harnessing innovation to help meet the needs of elders: field testing an electronic tool to streamline geriatric assessments across healthcare settings.

BACKGROUND: As populations age globally, effectively managing geriatric health poses challenges for primary care. Comprehensive geriatric assessments (CGAs) aim to address these challenges through multidisciplinary screening and coordinated care planning. However, most CGA tools and workflows have not been optimised for routine primary care delivery. OBJECTIVE: This study aimed to evaluate the impact of a computerised CGA tool, called the Golden Age Visit, implemented in primary care in Israel. METHODS: This study employed a quasiexperimental mixed-methods design to evaluate outcomes associated with the Golden Age electronic health assessment tool. Quantitative analysis used electronic medical records data from Maccabi Healthcare Services, the second largest health management organisation (HMO) in Israel. Patients aged 75 and older were included in analyses from January 2017 to December 2019 and January 2021 to December 2022. For patients, data were also collected on controls who did not participate in the Golden Age Visit programme during the same time period, to allow for comparison of outcomes. For physicians, qualitative data were collected via surveys and interviews with primary care physicians who used the Golden Age Visit SMARTEST e-assessment tool. RESULTS: A total of 9022 community-dwelling adults aged 75 and older were included in the study: 1421 patients received a Golden Age Visit CGA (intervention group), and 7601 patients did not receive the assessment (control group). After CGAs, diagnosis rates increased significantly for neuropsychiatric conditions and falls. Referrals to physiotherapy, occupational therapy, dietetics and geriatric outpatient clinics also rose substantially. However, no differences were found in rates of hip fracture or relocation to long-term care between groups. Surveys among physicians (n=151) found high satisfaction with the programme. CONCLUSION: Implementation of a large-scale primary care CGA programme was associated with improved diagnosis and management of geriatric conditions. Physicians were also satisfied, suggesting good uptake and feasibility within usual care. Further high-quality studies are still needed but these results provide real-world support for proactively addressing geriatric health needs through structured screening models.

A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.

We characterized an autosomal-recessive syndrome of focal epilepsy, dysarthria, and mild to moderate intellectual disability in a consanguineous Arab-Israeli family associated with subtle cortical thickening. We used multipoint linkage analysis to map the causative mutation to a 3.2 Mb interval within 16p13.3 with a LOD score of 3.86. The linked interval contained 160 genes, many of which were considered to be plausible candidates to harbor the disease-causing mutation. To interrogate the interval in an efficient and unbiased manner, we used targeted sequence enrichment and massively parallel sequencing. By prioritizing unique variants that affected protein translation, a pathogenic mutation was identified in TBC1D24 (p.F251L), a gene of unknown function. It is a member of a large gene family encoding TBC domain proteins with predicted function as Rab GTPase activators. We show that TBC1D24 is expressed early in mouse brain and that TBC1D24 protein is a potent modulator of primary axonal arborization and specification in neuronal cells, consistent with the phenotypic abnormality described.

Glucose transporter 1 deficiency in the idiopathic generalized epilepsies.

OBJECTIVE: We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs). METHODS: The IGEs are common, heritable epilepsies that usually follow complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood-brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced. RESULTS: Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE. INTERPRETATION: SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders.

Resolution of epileptic encephalopathy following treatment with transdermal nicotine.

We report resolution of an epileptic encephalopathy by administration of transdermal nicotine patches in an adolescent with severe nonlesional refractory frontal lobe epilepsy. The 18.5-year-old female patient had refractory epilepsy from the age of 11. Recurrent electroencephalography (EEG) recordings showed mostly generalized activity, albeit with right frontal predominance. Almost all antiepileptic medications failed to provide benefit. She developed an encephalopathic state with cognitive decline. The nonlesional frontal lobe epilepsy and a family history of a cousin with nocturnal epilepsy with frontal origin suggested genetic etiology. Transdermal nicotine patches brought complete resolution of the seizures, normalization of the EEG, and a significant improvement in her thinking process and speech organization. Sequencing of the CHRNB2 and CHRNA4 genes did not detect a mutation. Transdermal nicotine patches should be considered in severe pharmacoresistant frontal lobe epilepsy.

Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome.

Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS(+) ) in multiplex families and accounts for 70-80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS(+) families could be explained by highly penetrant SCN9A mutations.

Association between COVID-19 vaccination and critical outcomes among older adults with dementia: a comparative cohort study.

Background: As COVID-19 vaccines became available, understanding their potential benefits in vulnerable populations has gained significance. This study explored the advantages of COVID-19 vaccination in individuals with cognitive disorders by analyzing health-related variables and outcomes. Methods: A prospective cohort study analyzed electronic medical records of 25,733 older adults with cognitive disorders and 65,544 older adults without cognitive disorders from March 2020 to February 2022. COVID-19 vaccination status was the primary exposure variable, categorized as fully vaccinated or unvaccinated. The primary outcomes measured were all-cause mortality and hospitalization rates within 14 and 400 days post-vaccination. Data on vaccination status, demographics, comorbidities, testing history, and clinical outcomes were collected from electronic health records. The study was ethically approved by the relevant medical facility's Institutional Review Board (0075-22-MHS). Results: Vaccinated individuals had significantly lower mortality rates in both groups. In the research group, the mortality rate was 52% (n = 1852) for unvaccinated individuals and 7% (n = 1,241) for vaccinated individuals (p < 0.001). Similarly, in the control group, the mortality rate was 13.58% (n = 1,508) for unvaccinated individuals and 1.85% (n = 936) for vaccinated individuals (p < 0.001), despite higher COVID-19 positivity rates. In the research group, 30.26% (n = 1,072) of unvaccinated individuals tested positive for COVID-19, compared to 37.16% (n = 6,492) of vaccinated individuals (p < 0.001). In the control group, 17.31% (n = 1922) of unvaccinated individuals were COVID-19 positive, while 37.25% (n = 18,873) of vaccinated individuals tested positive (p < 0.001). Vaccination also showed potential benefits in mental health support. The usage of antipsychotic drugs was lower in vaccinated individuals (28.43%, n = 4,967) compared to unvaccinated individuals (37.48%, n = 1,328; 95% CI [0.92-1.28], p < 0.001). Moreover, vaccinated individuals had lower antipsychotic drug prescription rates (23.88%, n = 4,171) compared to unvaccinated individuals (27.83%, n = 968; 95% CI [-1.02 to -0.63], p < 0.001). Vaccination appeared to have a positive impact on managing conditions like diabetes, with 38.63% (n = 6,748) of vaccinated individuals having diabetes compared to 41.55% (n = 1,472) of unvaccinated individuals (95% CI [0.24, 0.48], p < 0.001). Discussion: The findings highlight the importance of vaccination in safeguarding vulnerable populations during the pandemic and call for further research to optimize healthcare strategies for individuals with cognitive disorders.

Delineation of the interstitial 6q25 microdeletion syndrome: refinement of the critical causative region.

Interstitial deletions of the long arm of chromosome 6 are rare. Clinically, this is a recognizable microdeletion syndrome associated with intellectual disability (ID), acquired microcephaly, typical dysmorphic features, structural anomalies of the brain, and nonspecific multiple organ anomalies. Most of the reported cases have cytogenetically visible interstitial deletions or subtelomeric microdeletions. We report on a boy with global developmental delay, distinct dysmorphic features, dysgenesis of the corpus callosum, limb anomalies, and genital hypoplasia who has a small interstitial deletion of the long arm of chromosome 6 detected by comparative genomic hybridization (CGH). The deleted region spans around 1 Mb of DNA and contains only two coding genes, ARID1B and ZDHHC14. To the best of our knowledge, this case represents the typical phenotype with the smallest deletion reported so far. We discuss the possible role of these genes in the phenotypic manifestations.

A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.

Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.

Mild adolescent/adult onset epilepsy and paroxysmal exercise-induced dyskinesia due to GLUT1 deficiency.

Paroxysmal exercise-induced dyskinesia (PED) and epilepsy without intellectual disability have recently been recognized as manifestations of deficiency of the glucose transporter GLUT1, due to mutations in the gene SLC2A1. We describe a family with six definitely affected members in two generations. Two had PED, three had epilepsy, and one had both. A missense mutation in SLC2A1 (c.950A>C; p.N317T) was detected in five living affected members, but absent in three nonaffected first-degree members and in one subject believed to be a phenocopy. The clinical picture of mild epilepsy with onset in adolescence or early adulthood plus PED should raise a suspicion of GLUT1 deficiency.